EP1998792B1 - Verfahren und zusammensetzungen in verbindung mit der synthese zyklischer peptide - Google Patents

Verfahren und zusammensetzungen in verbindung mit der synthese zyklischer peptide Download PDF

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EP1998792B1
EP1998792B1 EP07757735.1A EP07757735A EP1998792B1 EP 1998792 B1 EP1998792 B1 EP 1998792B1 EP 07757735 A EP07757735 A EP 07757735A EP 1998792 B1 EP1998792 B1 EP 1998792B1
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peptide
seq
cell
sequence
disclosed
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EP1998792A2 (de
EP1998792A4 (de
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Eric W. Schmidt
Brian Hathaway
James T. Nelson
Mohamed Samir Donia
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University of Utah Research Foundation Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • Marine invertebrates particularly sponges and ascidians, are well known for their production of bioactive natural products ( Newman et al.(2005) Mol. Cancer Ther. 4, 333-342 ..
  • a major hurdle in the development of many of these agents into drugs has been their supply, since collection or aquaculture of marine invertebrates pose many difficulties and may not be environmentally acceptable.
  • marine invertebrate compounds often resemble molecules isolated from bacteria, many compounds are synthesized by symbiotic bacteria and not by the animals themselves ( Faulkner et al. (1993) Gazz. Chim. Ital. 123, 301-307 ; Kobayashi et al. (1993) Chem. Rev. 93, 1753-1770 ; Sings et al. (1996) J.
  • Bacterial secondary metabolites are bioactive small molecules that often find use as pharmaceuticals. ( Newman et al. J. Nat. Prod. 66, 1022-1037 (2003 )). Numerous studies of secondary metabolite biosynthetic genes have led to an increasing ability to synthesize new small molecules through rational pathway engineering ( Floss J. Biotechnol. epub (2006 ); Walsh, C. T. ChemBioChem, 124-134 (2002 )). Much of this capability comes from gene sequence comparison, in which the observation of evolution of these pathways has enabled engineering. Despite the advances, a weakness of this approach is that most described pathways are relatively distantly related, making an analysis of single evolutionary events difficult to discern. This difficulty is compounded by the large number of dedicated enzymatic steps (up to approximately 60 or so) commonly required to synthesize individual secondary metabolites.
  • pat was originally cloned from an environmental (uncultured) bacterial sample, and the intact pathway produced low levels of patellamides. Therefore , patA-G were cloned and expressed in compatible DUET vectors in E. coli.
  • PatA, PatD, PatE, and PatG would be required for patellamide biosynthesis.
  • PatE as the direct patellamide prepeptide, is obviously a required precursor.
  • PatD has low sequence similarity to a series of enzymes involved in thiazole formation in a group of microcins, ( Roy et al. Nat. Prod. Rep. 1999, 16, 249-263 ; Milne et al.
  • patE3 contained sequences encoding lissoclinamides, compounds composed of seven amino acids for which no biosynthetic machinery had been previously described ( WO 90/05731 ).
  • An ascidian Lissoclinum patella from Papua New Guinea, contained patE3 and was selected for detailed chemical analysis. From this sample, lissoclinamides 2-4 and the related ulicyclamide were purifed to homogeneity and characterized by 1 H NMR and mass spectrometry. Lissoclinamides 2 and 4 are directly encoded by patE3.
  • N can be any length
  • the remaining sequence is a recognition sequence which allows for the cyclization of whichever peptide is placed in the "N" position
  • the isolated peptide can also comprise an amino acid segment comprising the amino acid sequence of SEQ ID NO: 52 (GVDASN 1 SYDGVDAS, where N is the coding sequence and can be any length). Also disclosed is an isolated peptide comprising an amino acid segment comprising the amino acid sequence of SEQ ID NO: 53 (SYDGVDASN 2 SYDD where N is the coding sequence and can be any length).
  • variants of genes and proteins herein disclosed typically have at least, about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent homology to the stated sequence or the native sequence.
  • the homology can be calculated after aligning the two sequences so that the homology is at its highest level.
  • nucleic acids are designed to interact with other nucleic acids based on sequence homology between the target molecule and the functional nucleic acid molecule.
  • the specific recognition between the functional nucleic acid molecule and the target molecule is not based on sequence homology between the functional nucleic acid molecule and the target molecule, but rather is based on the formation of tertiary structure that allows specific recognition to take place.
  • substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct.
  • the mutations must not place the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure.
  • substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Tables 1 and 2 and are referred to as conservative substitutions.
  • a polypeptide comprising inserting the polypeptide to be cyclized in the coding region of a fusion polypeptide.
  • SEQ ID NO: 1 GLEASN 1 AYDGVEPSK 2 AYDGE
  • a coding sequence such as a sequence encoding a peptide to by cyclized.
  • the entire sequence is known as a fusion polypeptide.
  • the coding region is often referred to herein as a peptide, it can be any polymer capable of being cyclized. It is known in the art that any type of polymer can be cyclized using the methods disclosed herein, including organic polymers such as biopolymers that contain amino acid or nucleotide monomers, or a mixture of different types of monomers. Accordingly, polypeptides, polynucleotides, or a polymer containing both amino acid and nucleotide monomers, for example, may be cyclized using the subject methods.
  • the polymer used is a biopolymer containing amino acids, i.e., a polypeptide. Polymers that may be employed in the subject methods may not contain any peptide bonds. However, in certain embodiments, the polymers may contain peptide bonds in between the first and second monomers of one or both ends of the polymer to be cyclized.
  • a representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, kidney cancer, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon and rectal cancers, prostatic cancer, or pan
  • a methanolic extract (57 mg) was partially purified by step gradient on a column containing 7 g C 18 , using solvents containing 0.01% trifluoroacetic acid. Fractions were eluted with water, followed by 25%, 50% and 100% acetonitrile (aq). The 100% elution fraction was further purified on a Phenomenex C 18 column as described before. A single peak with the correct diode array profile cleanly eluted at 16.6 min. By ESI-MS analysis, this HPLC-peak contained the 1099 ion.
  • Example 3 Rapid recombination of secondary metabolic pathways in marine symbiotic bacteria
  • patE encodes a peptide of 71 amino acids, the first 37 of which are proposed to serve as a leader sequence for processing ( Figure 16 ). Of the remaining 34 amino acids, 16 directly encode the patellamide C and A sequences, while 18 make up motifs that we propose direct the cyclization of patellamides.
  • the patellamide C peptide is located 8 amino acids upstream of the patellamide A sequence. Prior to both peptides, there is a 5-amino acid conserved region consisting of the consensus G(L/V)E(A/P)S (SEQ ID NO: 40).
  • the sequence AYDGE terminates the patellamide A sequence and directly precedes the stop codon.

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Claims (16)

  1. Ein isoliertes Peptid aufweisend ein Aminosäuresegment aufweisend die Aminosäuresequenz von SEQ ID NR.: 1 oder die Aminosäuresequenz von SEQ ID NR.: 1 mit einer oder mehreren konservativen Aminosäuresubstitutionen, wobei Xaa an Position 6 und Xaa an Position 15 von SEQ ID NR.: 1 eine Länge von 6, 7, 9 oder 10 Aminosäuren haben, wobei eine konservative Aminosäuresubstitution eine ausgewählt von innerhalb der folgenden Gruppierungen ist:
    Gly, Ala
    Val, Ile, Met, Leu
    Asp, Glu
    Asn, Gln, His
    Ser, Thr
    Lys, Arg
    Phe, Tyr, Trp.
  2. Ein isoliertes Peptid aufweisend ein Aminosäuresegment aufweisend die Aminosäuresequenz von SEQ ID NR.: 2 oder 3 oder die Aminosäuresequenz von SEQ ID NR.: 2 oder 3 mit einer oder mehreren konservativen Aminosäuresubstitutionen, wobei Xaa an Position 6 von SEQ ID NR.: 2 und Xaa an Position 9 von SEQ ID NR.: 3 eine Länge von 6, 7, 9 oder 10 Aminosäuren haben, wobei eine konservative Aminosäuresubstitution eine ausgewählt von innerhalb der folgenden Gruppierungen ist:
    Gly, Ala
    Val, Ile, Met, Leu
    Asp, Glu
    Asn, Gln, His
    Ser, Thr
    Lys, Arg
    Phe, Tyr, Trp.
  3. Ein Vektor aufweisend eine Nukleotidsequenz, die ein Fusionspolypeptid kodiert, das, angeordnet von N-terminus zu C-terminus, aufweist: a) eine C-terminale Domäne aufweisend SEQ ID NR.: 10; b) ein Peptid; c) eine N-terminale Domäne aufweisend SEQ ID NR.: 11; wobei das besagte Peptid eine Länge von 6, 7, 9 oder 10 Aminosäuren hat und wobei das Fusionspeptid das Peptid cyclisieren kann, wenn es zusammen mit einem Genset exprimiert wird, das zumindest patA, patD, patF und patG aufweist, um ein cyclisches Peptid in einer Säugetierzelle herzustellen.
  4. Ein Vektor aufweisend eine Nukleotidsequenz, die ein Fusionspolypeptid kodiert, das, angeordnet von N-terminus zu C-terminus, aufweist: a) eine C-terminale Domäne aufweisend SEQ ID NR.: 11; b) ein Peptid; c) eine N-terminale Domäne aufweisend SEQ ID NR.: 12; wobei das besagte Peptid eine Länge von 6, 7, 9 oder 10 Aminosäuren hat und wobei das Fusionspeptid das Peptid cyclisieren kann, wenn es zusammen mit einem Genset exprimiert wird, das zumindest patA, patD, patF und patG aufweist, um ein cyclisches Peptid in einer Säugetierzelle herzustellen.
  5. Ein Vektor aufweisend eine Nukleotidsequenz, die ein Fusionspolypeptid kodiert, das, angeordnet von N-terminus zu C-terminus, aufweist: a) eine C-terminale Domäne aufweisend SEQ ID NR.: 10; b) ein Peptid; c) eine N-terminale Domäne aufweisend SEQ ID NR.: 12; wobei das besagte Peptid eine Länge von 6, 7, 9 oder 10 Aminosäuren hat und wobei das Fusionspeptid das Peptid cyclisieren kann, wenn es zusammen mit einem Genset exprimiert wird, das zumindest patA, patD, patF und patG aufweist, um ein cyclisches Peptid in einer Säugetierzelle herzustellen.
  6. Eine Bibliothek von Vektoren von einem der Ansprüche 3 - 5, bei der jeder Vektor in der Bibliothek ein unterschiedliches Fusionspolypeptid kodiert.
  7. Die Bibliothek von Anspruch 6, bei der das Peptid von Interesse von jedem unterschiedlichen Fusionspolypeptid unterschiedlich ist.
  8. Eine Zelle aufweisend den Vektor von einem der Ansprüche 3 - 5.
  9. Die Zelle von Anspruch 8, welche eine prokaryotische Zelle ist.
  10. Die Zelle von Anspruch 8, welche eine eukaryotische Zelle ist.
  11. Die Zelle von Anspruch 10, welche eine Säugetierzelle ist.
  12. Die Zelle von Anspruch 10, welche ausgewählt wird aus der Gruppe bestehend aus einer Tumorzelle, einer Leberzelle, einem Hepatozyt, einer Mastzelle und einer Lymphozytzelle.
  13. Die Zelle von Anspruch 10, welche eine menschliche Zelle ist.
  14. Ein Verfahren zum Cyclisieren eines Polypeptids, das Verfahren aufweisend Einfügen des Polypeptids, das cyclisiert werden soll, in die Xaa an Position 6 oder die Xaa an Position 15 von SEQ ID NR.:
    1 und Exprimieren des besagten Peptids, das in SEQ ID NR.: 1 eingefügt wurde, zusammen mit einem Genset aufweisend zumindest patA, patD, patF und patG, wobei das Polypeptid, das cyclisiert werden soll, eine Länge von 6, 7, 9 oder 10 Aminosäuren hat.
  15. Ein Verfahren zum Cyclisieren eines Polypeptids, das Verfahren aufweisend Einfügen des Polypeptids, das cyclisiert werden soll, in die Xaa an Position 6 von SEQ ID NR.: 2 oder in die Xaa an Position 9 von SEQ ID NR.: 3 und Exprimieren des besagten Peptids, das in die SEQ ID NR.: 2 oder 3 eingefügt wurde, zusammen mit einem Genset aufweisend zumindest patA, patD, patF und patG, wobei das Polypeptid, das cyclisiert werden soll, eine Länge von 6, 7, 9 oder 10 Aminosäuren hat.
  16. Ein Verfahren zum Cyclisieren eines Polypeptids, das Verfahren aufweisend Exprimieren des Vektors von einem der Ansprüche 3 - 5 zusammen mit einem Genset aufweisend zumindest patA, patD, patF und patG.
EP07757735.1A 2006-03-01 2007-03-01 Verfahren und zusammensetzungen in verbindung mit der synthese zyklischer peptide Active EP1998792B1 (de)

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PCT/US2007/063089 WO2007103739A2 (en) 2006-03-01 2007-03-01 Methods and compositions related to cyclic peptide synthesis

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US10197567B2 (en) 2011-03-09 2019-02-05 The University Of Tokyo Azoline compound and azole compound library and method for producing same
WO2012162512A1 (en) * 2011-05-26 2012-11-29 Novobiotic Pharmaceuticals Llc Novel antibiotics
US9394561B2 (en) 2011-12-07 2016-07-19 National Research Council Of Canada Cyclic peptide production
GB201211617D0 (en) 2012-06-29 2012-08-15 Univ Aberdeen Production of cyclic peptides
US10329558B2 (en) 2013-03-07 2019-06-25 The University Of Tokyo Method for producing compound containing heterocycle
DK2986635T3 (en) 2013-04-18 2019-01-28 Fond Telethon EFFECTIVE DELIVERY OF BIG GENES THROUGH DUAL-AAV VECTORS
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WO1990005731A1 (en) * 1988-11-24 1990-05-31 University Of Queensland Cytotoxic macromolecules

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US20160326217A1 (en) 2016-11-10
WO2007103739A2 (en) 2007-09-13
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US20090215172A1 (en) 2009-08-27
WO2007103739A3 (en) 2008-03-20
EP1998792A2 (de) 2008-12-10
EP1998792A4 (de) 2011-08-31
AU2007223427A1 (en) 2007-09-13

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